OBJECTIVE: To find biomarkers identifying patients at risk for the development of progressive multifocal leukoencephalopathy (PML) during natalizumab treatment.METHODS: Patients were recruited from 10 European and US cohorts. Of 289 patients with multiple sclerosis (MS), 224 had been treated with natalizumab (18-80 months), 21 received other immune-modulatory treatments, and 28 were untreated. We had access to samples from 16 natalizumab PML patients. Eight of these patients had given blood before the diagnosis of PML. We also analyzed non-natalizumab-treated patients who developed PML (n = 10) and age- and sex-matched healthy donors (n = 31). All flow cytometric assessments were done on previously cryopreserved, viable peripheral blood mononuclear cells.RESULTS: The percentage of l-selectin-expressing CD4+ T cells was significantly lower in patients treated long-term with natalizumab (40.2%) when compared with patients not receiving natalizumab treatment (47.2%; p = 0.016) or healthy controls (61.0%; p < 0.0001). An unusually low percentage (9-fold lower; 4.6%) was highly correlated with the risk of developing PML in the patient group with available pre-PML samples when compared with non-PML natalizumab-treated patients (p ≤ 0.0001). Samples were gathered between 4 and 26 months before PML diagnosis.CONCLUSIONS: The cell-based assessment of the percentage of l-selectin-expressing CD4 T cells could provide an urgently needed biomarker for individual PML risk assessment.

L selectin (CD62L) is a carbohydrate that is involved in cell migration into lymph glands. Cells that have not been stimulated by their target antigen have high levels of CD62L on their surface and so are able to enter lymph glands through specialised blood vessels called High endothelial venules. When cells become activated they down regulate CD62L and upregulate another molecule called CD44 as well as others such as CD45RO.

CD44 binds to hyaluronic acid that gets made/deposited in peripheral tissues and so the migratory profile changes such that the white blood cells are not preferentially drawn into lymph glands which is where they are stimulated to become activated, but get drawn into inflammed tissues. They also use CD49d or VLA-4 to do this. As the CD49d inhibiting antibody (Tysabri) works by stopping geeting white blood cells into the brain,it will mean that CD49d expressing cells get trapped in the blood. These have low CD62L and so the relative percentage of CD62L expressing cells will drop.

It was found that people with a very low level of CD62L (about 5% verses 60% in healthy people and 40% in Tysabrians, in their blood have a higher risk of PML. This could be because the drug is more effective at stopping the cells getting into the brain. If this simple biomarker pans out it could be very useful as it is a simple test that one could done in the lab within an hour after taking a blood sample.

Maybe this is something that needs to be done prospectively and see how common such a low level of CD62L is.

PML Risk Infographic

Holistic Management of MS ver. 7.0

Search this Blog

Follow by Email

Subscribe To

Translate

Followers

Disclaimer

General Disclaimer: Please note that the opinions expressed here are those of the individual bloggers and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry, Queen Mary University of London or Barts Health NHS Trust.

Survey Disclaimer: No personal identifiers will be collected as part of these surveys. By completing these surveys you are consenting to the data you provide being analysed by Professors Giovannoni and Baker and their collaborators. Results of these surveys will be presented on this blog and may be submitted for publication.